Motor neuron diseases, including ALS and SMA, are featured by degeneration and death of lower motor neurons. Significant progress in genetics has allowed for the construction of spectacular transgenic models, but the basic pathogenic mechanisms of these illnesses remain unknown and there are no disease-modifying treatments. Cell death prevention strategies, including the use of trophic factors and small neuroprotective molecules, have had very limited clinical success. Perhaps the greatest promise lies in cell replacement strategies, based on our preliminary findings that exogenous neural stem cells (NSCs) can become avidly engrafted in the adult rat spinal cord and give rise to cells with clinically relevant phenotypes, i.e. neurons and ensheathing cells. Encouraged by these findings, we propose a stepwise approach to ensure that rodent and human NSCs differentiate into neurons and glia when transplanted at the sites of degenerated motor neurons in rat spinal cord after excitotoxic applications and in the ventral horn of transgenic animals which show the clinical features of ALS, i.e. SOD1 transgenic rodents. We are interested in the ability of NSC-derived neurons, suggested by our preliminary findings, to receive excitatory and inhibitory innervation and extend axons to ventral roots towards muscle targets. We expect that the restitution of the degenerating neuromuscular units will improve muscle strength in SOD1 transgenic animals, as assessed by behavioral testing on motorized devices. In concert, we propose to examine the essential preclinical parameters for the consideration of NSCs as therapeutic tools for motor neuron disease.